Abstract: OBJECTIVE To study the interaction between Wortmannnin, a selective inhibitor of PIKKs, and TSA, to explore the role of DNA damage signals in HDIs induced tumor cell death. METHODS The cell cycle distribution and cell apoptosis were detected by flow cytometry. The expression level of Caspase-2, 3, 7 and Survivin were determined by Western blotting with the antibody against each protein. RESULTS While low-dose Wortmannin alone had little effect on the tumor cell viability, it inhibited Trichostatin A (TSA) induced G₂/M arrest and enhanced TSA induced apoptosis. TSA induced human acute lymphoblastic leukemia (MOLT-4) cells apoptosis through activation of Caspase-2, 3, 7. When pretreatment with Wortmannin, activation of Caspase-2, Caspase-3, and Caspase-7 by TSA was accelerated, and Survivin, a member of inhibitor of apoptosis protein (IAP) family, was also significantly decreased coincident with the acceleration of cells apoptosis. CONCLUSION As a PIKKs inhibitor, wortmannnin has been proposed as a potential anti-neoplastic agent. Wortmannin enhances TSA-induced tumor cells apoptosis through down-regulation of Survivin and activation of Caspase-cascades.